This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. Rheumatoid Arthritis (RA) is an autoimmune disease that affects joints, leading to joint destruction, significant morbidity and increased mortality. Analysis of other autoimmune diseases has shown that the majority of individuals that are ultimately clinically affected with these conditions exhibit three sequential phases of disease progression: 1) Carriage of genetic risk primarily through HLA associations, 2) Presence of clinically silent autoantibodies for one or more years, and 3) Clinically apparent target organ injury. Studies of autoimmune disease evolution whose primary outcome measures are disease-related autoimmunity in asymptomatic individuals, rather than clinically apparent disease itself, can provide unique insights into pathogenesis because they are accomplished without substantial recall bias or the untoward effects of clinically active disease and target organ damage. We propose that RA also exhibits these phases of disease and that analysis of epidemiologic associations within the genetically at-risk and autoantibody positive but clinically unaffected individuals will provide important insights into the pathogenesis of this disease. To address these issues, we propose a study in which we will recruit a population of first degree relatives (FDR) of individuals with RA. We will utilize this cohort to obtain relevant genetic and epidemiologic data and accomplish the following primary specific aims: Specific Aim #1: In unaffected FDRs of individuals with RA, determine the association between the carriage of high risk HLA alleles and the presence of RA-related autoantibodies. Specific Aim #2: In this population of unaffected FDRs, determine the association between epidemiologic exposures and the presence of RA-related autoantibodies.